Noninvasive gamma detection methods and positron emission tomography (PET) have been used to monitor transvascular flux of proteins in the lung. However, neither method has gained widespread clinical use. Although PET can measure regional variations in vascular permeability, its high cost, limited availability, and lengthy scan times currently confine PET permeability measurements to a research tool. Portable gamma detection systems are very inexpensive, and can be easily moved to the bedside, but suffer from artifacts introduced by long scan times and contributions of other organs to detected radioactivity. The purpose of this investigation is to make improvements which might transform these techniques into clinically useful tools. Specifically, we propose to shorten scan times in PET studies by labeling 5-40 kDa dextrans with F-18, and in portable gamma studies by labeling dextrans with Tc-99m and F-18. Moreover, quantitative evaluation of lung vascular permeability will be significantly improved by comparing the flux of two or more radiolabelled dextrans having different molecular size or different electrical charge. Simultaneous comparisons of lung transvascular flux will be made in rabbits using the external gamma detection technique. The most promising dextrans will be used in humans with known lung abnormalities, and their flux, measured with portable detectors, compared simultaneously with albumin transport. The contribution of chest wall activity to external gamma detection will also be measured. A noninvasive method for computing the ratio of interstitial to plasma solute concentration (I/P) is developed, and measurements of I/P will be compared with steady-state lymph/plasma concentrations of fluorescent dextrans infused in sheep with lung lymph fistulae. Finally, a mathematical model will be applied to fluorescent dextran and noninvasive protein and dextran flux measurements to provide a quantitative measure of lung vascular permeability. Preliminary results indicate that at least two equivalent pore sizes (radii of 3 nm and 11.5 nm) are needed to describe dextran lung lymph concentrations. The model will be expanded to account for electrical charge and 3-D regional inhomogeneities, and will be applied to sheep unilateral lung injury studied with gamma probes. We anticipate that the results of this study will lead to a better understanding of the lung transvascular barrier, and will provide a simple, inexpensive method for directly monitoring lung vascular permeability.